Germline BRCA1/2 Mutations and p27Kip1 Protein Levels Independently Predict Outcome After Breast Cancer

Abstract

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27Kip1 in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27Kip1 protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27Kip1 expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27Kip1 expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P = .009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P = .003). Similar results were seen for women whose tumors expressed low levels of p27Kip1, compared with those with high levels (5-year DDFS, 68% v 93%; P < .0001). In a multivariate analysis, both BRCA1/2 mutation and low p27Kip1 expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P = .05; and RR, 3.9; 95% CI, 1.4 to 11.1; P = .01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27Kip1 in breast cancer. Both BRCA1/2 and p27Kip1 status were identified as independent prognostic factors.